Small molecule induction of MSH2-dependent cell death suggests a vital role of mismatch repair proteins in cell death.
Avoidance of apoptosis is one of the hallmarks of cancer development and progression. Chemotherapeutic agents aim to initiate an apoptotic response, but often fail due to dysregulation. MSH proteins are capable of recognizing cisplatin damage in DNA and participate in the initiation of cell death. We have exploited this recognition and computationally simulated a MutS homolog (MSH) "death conformation". Screening and docking experiments based on this model determined that the MSH2-dependent cell-death pathway can be induced by a small molecule without DNA damage, reserpine. Reserpine was identified via virtual screening on structures obtained from molecular dynamics as a small molecule that selectively binds a protein "death" conformation. The virtual screening predicts that this small molecule binds in the absence of DNA. Cell biology confirmed that reserpine triggers the MSH2-dependent cell-death pathway. This result supports the hypothesis that the MSH2-dependent pathway is initiated by specific protein conformational changes triggered by binding to either DNA damage or small compound molecules. These findings have multiple implications for drug discovery and cell biology. Computational modeling may be used to identify and eventually design small molecules that selectively activate particular pathways through conformational control. Molecular dynamics simulations can be used to model the biologically relevant conformations and virtual screening can then be used to select for small molecules that bind specific conformations. The ability of a small molecule to induce the cell-death pathway suggests a broader role for MMR proteins in cellular events, such as cell-death pathways, than previously suspected.
Vasilyeva
Aksana
A
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States.
Clodfelter
Jill E
JE
Rector
Brian
B
Hollis
Thomas
T
Scarpinato
Karin D
KD
Salsbury
Freddie R
FR
D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D003198:Computer Simulation; D053843:DNA Mismatch Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D011487:Protein Conformation; D012110:Reserpine / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C098790:MSH6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D012110:Reserpine; D053148:Caspase 3; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein; D002945:Cisplatin